Examples of progress made during the prior year are summarized below. 1. 11C-(R)-rolipram PET detects Disc1 inhibition of phosphodiesterase type 4 (PDE4) in living Disc1 locus-impaired mice Phosphodiesterase type 4 (PDE4), a key enzyme that metabolizes second messenger cyclic adenosine monophosphate (cAMP), is regulated by protein kinase A (PKA) and the protein Disrupted in Schizophrenia 1 (DISC1). In positron emission tomography (PET) studies, 11C-(R)-rolipram was used to visualize the activation of PDE4 by PKA. Because DISC1 is hypothesized to inhibit PDE4 activation, the absence of DISC1 would be expected to increase PDE4 activity. A recent study from our group used a Disc1 locus impairment (LI) mouse model to investigate whether 11C-(R)-rolipram PET imaging could quantify the interaction between PDE4 and DISC1. In vitro enzymatic assays in the brains of these animals were used to confirm changes in PDE4 activity observed via PET imaging. We found that Disc1 LI mice showed a 41% significant increase in distribution volume (VT) compared to wild-type mice. VT/fP, which more accurately reflects 11C-(R)-rolipram binding than VT, showed a 73% significant increase in Disc1 LI compared to wild-type mice. We observed significant group differences in PDE4 enzyme activity; the activity levels of LI mice were greater than those of heterozygotes which, in turn, were greater than the activity levels of wild-type mice. Our findings demonstrate a clear increase in PDE4 activity in the absence of most critical Disc1 protein isoforms both in vivo and ex vivo. In addition, 11C-(R)-rolipram PET imaging was sensitive enough to assess differences in PDE4 activity caused by the interaction between PDE4 and DISC1. These data warrant further investigation into the potential biological activity of DISC1 isoforms. 2. 18FOGA1 is a promising PET radioligand for measuring O-GlcNAcase in brain Strong evidence suggests that the accumulation and spread of misfolded, insoluble taua microtubule-associated protein that regulates axonal microtubule structure and function in neuronsplays an important role in the progression of Alzheimers disease. Inhibiting O-GlcNAcase an enzyme that deglycosylates intracellular proteins including tau is a key strategy for treating AD and related tauopathies. We developed a novel radioligand that binds to O-GlcNAcase: 18FOGA1. The ligand was synthesized and evaluated in rhesus monkey brain at baseline and after pretreatment with either thiamet-G, a potent O-GlcNAcase inhibitor, or the cold parent compound (self-blocking). Positron emission tomography (PET) imaging was performed and brain O-GlcNAcase knockout mice were also scanned to confirm specificity of the radioligand. We found that, in monkeys at baseline, brain uptake peaked around 5 SUV followed by slow washout. The highest uptake was observed in striatum followed by frontal cortex, hippocampus, thalamus, and cerebellum. After pretreatment with thiamet-G or cold parent, brain uptake was reduced to background levels in all regions; distribution volume (VT) decreases of > 90% were observed. Brain uptake of 18FOGA1 in wild-type mice at baseline was significantly higher than in O-GlcNAcase knockout mice. Pretreatment with thiamet-G reduced brain uptake in wild-type mice to the levels observed in O-GlcNAcase knockout mice; no further decreases were seen in the O-GlcNAcase knockout mice following pretreatment with thiamet-G. The effective dose for humans was estimated to be 21.8 mSv/MBq, which is well within the acceptable safety limits for 18F-labeled radioligands. Taken together, our results show that 18FOGA1 is a promising PET radioligand for measuring O-GlcNAcase in brain, and provides a potentially important tool for monitoring the treatment of tauopathies in Alzheimers disease. 3. Novel PET radioligands show that COX-1 is constitutively expressed and that COX-2 is induced by inflammation in rhesus macaque. The cyclooxygenase (COX) system is implicated in the pathophysiology of brain diseases, including Alzheimer's disease and depression, and is a potential biomarker for neuroinflammation. The COX system comprises two isoforms, COX-1 and COX-2, which are key enzymes in neuroinflammation. We recently developed two PET radioligands: 11C-PS13 for COX-1 and 11C-MC1 for COX-2. Building on this work, a recent study from our laboratory explored the in vivo expression of COX-1 and COX-2 with the new radioligands in rhesus monkeys. The study was divided into two parts: whole-body PET/CT in normal monkeys and brain PET in monkeys with neuroinflammation. To induce transient neuroinflammation, lipopolysaccharide (LPS) was injected into the right putamen of monkeys. After intravenous injection of either radioligand into rhesus monkeys, dynamic whole-body or brain PET scans were obtained. To measure the specific uptake, we performed both baseline and blockade scans. As blockers, we used non-radioactive PS13, non-radioactive MC1, and aspirin, a preferential inhibitor of COX-1. We found that, under normal conditions, 11C-PS13 showed specific uptake in spleen, gastrointestinal tract, and brain while 11C-MC1 showed uptake only in brown adipose tissue. After putaminal injection of LPS, 11C-PS13 uptake was not increased in brain but 11C-MC1 uptake was significantly increased. Our results suggest that COX-1 is constitutively expressed in major organs while COX-2 is only induced by inflammation. Different patterns of expression between two COX isoforms were successfully demonstrated by 11C-PS13 and 11C-MC1, suggesting that these two radioligands show promise as biomarkers for measuring inflammation in various disorders, as well as target engagement of therapeutic drugs.